A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology

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  • Anja E Pen, Denmark
  • Mette Nyegaard
  • Mingyan Fang, BGI-Shenzhen, Shenzhen, China., China
  • Hui Jiang, BGI-Shenzhen, Shenzhen, China., Shenzhen Key Laboratory of Genomics, The Guangdong Enterprise Key Laboratory of Human Disease Genomics, China
  • Rikke Christensen
  • Henning Mølgaard
  • Henning Andersen
  • Benedicte Parm Ulhøi, Denmark
  • John R Østergaard
  • Signe Væth
  • Mette Sommerlund
  • Arjan P M de Brouwer, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Netherlands
  • Xiuqing Zhang, BGI-Shenzhen, Shenzhen, China., Shenzhen Key Laboratory of Genomics, The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Unknown
  • Uffe B Jensen

We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resurrected from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25 Mb from 123.6 Mb to 148.4 Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A>T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. (2013).

Original languageEnglish
JournalEuropean Journal of Medical Genetics
Volume58
Issue4
Pages (from-to)222-229
Number of pages8
ISSN1769-7212
DOIs
Publication statusPublished - Apr 2015

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